Synthesis of (-)-epibatidine

Article abstract of DOI:10.1021/ol016420q

matrix presented The synthesis of (-)-epibatidine has been accomplished utilizing a highly exo-selective asymmetric hetero Diels-Alder reaction. The key steps employed to transform the resulting bicycle into the natural product include a fluoride-promoted fragmentation and a Hofmann rearrangement.

Full text of DOI:10.1021/ol016420q

ORGANIC
LETTERS
2001
Vol. 3, No. 19
3009-3012
Synthesis of (−)-Epibatidine
David A. Evans,* Karl A. Scheidt, and C. Wade Downey
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
eVans@chemistry.harVard.edu
Received July 10, 2001
ABSTRACT
The synthesis of (−)-epibatidine has been accomplished utilizing a highly exo-selective asymmetric hetero Diels−Alder reaction. The key steps
employed to transform the resulting bicycle into the natural product include a fluoride-promoted fragmentation and a Hofmann rearrangement.
In 1992, Daly and co-workers disclosed the structure of
epibatidine (1), an alkaloid isolated from the skin of the
Ecuadorian frog Epibatidores tricolor.1 Because of its
scarcity and unprecedented biological activity as a nonopiate
analgesic approximately 200 times more potent than mor-
phine,2 widespread efforts have culminated in numerous total
and formal syntheses.3 Surprisingly, while approximately 50
syntheses have been reported, few full syntheses are enantio-
selective.4 In this Letter, we wish to report a highly
stereoselective synthesis of (-)-epibatidine by a route that
is readily amenable to analogue production.
Our approach to 1 relies on a selective hetero Diels-Alder
reaction between bis-silyloxy azadiene 45 and an unsaturated
acyl oxazolidinone (3) appended to the requisite chloro-
pyridine ring (Scheme 1). We anticipated that this Diels-
Alder reaction promoted by Me2AlCl would exhibit high
levels of facial selectivity due to the rigid chelate of the
activated acyl oxazolidinone.6 Furthermore, previous con-
tributions by Ghosez and co-workers have established that
Diels-Alder reactions utilizing 2-azadienes such as 4 are
highly exo-selective.5 The union of these two control
elements would afford an appropriately functionalized
2-azabicyclo[2.2.2]octanone 2.
(1) (a) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.;
Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475-3478. (b)
Daly, J. W.; Garraffo, H. M.; Spande, T. F.; Decker, M. W.; Sullivan, J.
P.; Williams, M. Nat. Prod. Rep. 2000, 17, 131-135.
(2) (a) Badio, B.; Daly, J. W. Mol. Pharmacol. 1994, 45, 563-568. (b)
Ellis, J. L.; Harman, D.; Gonzalez, J.; Spera, M. L.; Liu, R.; Shen, T. Y.;
Wypij, D. M.; Zuo, F. J. Pharmacol. Exp. Ther. 1999, 288, 1143-1150.
(c) Kesingland, A. C.; Gentry, C. T.; Panesar, M. S.; Bowes, M. A.; Vernier,
J. M.; Cube, R.; Walker, K.; Urban, L. Pain 2000, 86, 113-118 and
references therein.
(3) For early total syntheses of epibatidine, see: (a) Broka, C. A.
Tetrahedron Lett. 1993, 34, 3251-3254. (b) Huang, D. F.; Shen, T. Y.
Tetrahedron Lett. 1993, 34, 4477-4480. (c) Fletcher, S. R.; Baker, R.;
Chambers, M. S.; Hobbs, S. C.; Mitchell, P. J. J. Chem. Soc., Chem.
Commun. 1993, 1216-1218. (d) Corey, E. J.; Loh, T. P.; AchyuthaRao,
S.; Daley, D. C.; Sarshar, S. J. Org. Chem. 1993, 58, 5600-5602. (e)
Clayton, S. C.; Regan, A. C. Tetrahedron Lett. 1993, 34, 7493-7496. For
reviews on the total syntheses of epibatidine, see: Chen, Z.; Trudell, M. L.
Chem. ReV. 1996, 96, 1179-1193. For a recent synthesis, see: Barros, M.
T.; Maycock, C. D.; Ventura, M. R. J. Chem. Soc., Perkin Trans. 1 2001,
166-173.
Scheme 1. Epibatidine Retrosynthesis
(4) For enantioselective total syntheses of epibatidine, see: (a) Hernandez,
A.; Marcos, M.; Rapoport, H. J. Org. Chem. 1995, 60, 2683-2691. (b)
Trost, B. M.; Cook, G. R. Tetrahedron Lett. 1996, 37, 7485-7488. (c)
Sza´ntay, C.; Kardos-Balogh, Z.; Moldvai, I.; Sza´ntay, C., Jr.; Temesve´ri-
Major, E.; Blasko´, G. Tetrahedron 1996, 52, 11053-11062. (d) Kosugi,
H.; Abe, M.; Hatsuda, R.; Uda, H.; Kato, M. Chem. Commun. 1997, 1857-
1858. (e) Aoyagi, S.; Tanaka, R.; Naruse, M.; Kibayashi, C. Tetrahedron
Lett. 1998, 39, 4513-4516. (f) Jones, C. D.; Simpkins, N. S.; Giblin, G.
M. P. Tetrahedron Lett. 1998, 39, 1023-1024.
10.1021/ol016420q CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/30/2001

The synthesis of acyl oxazolidinone dienophile 7 began
with a Horner-Wadsworth-Emmons reaction of aldehyde
57 and phosphonate 68 using Masamune-Roush conditions
(LiCl, i-Pr2EtN, CH3CN, Scheme 2).9 The desired R,â-
the dienophile. The azadiene’s preference for an exo ap-
proach (TS1) over an endo approach (TS2) is likely
attributable to steric interactions between one of the triethyl-
silyloxy substituents of 8 and the aluminum Lewis acid. The
stereochemistry of 9 was unambiguously established by
X-ray crystallography (Figure 1).
Scheme 2. Asymmetric Hetero Diels-Alder Reactiona
a Reaction conditions: (a) LiCl, i-Pr2EtN, CH3CN. (b) Me2AlCl
(2.2 equiv), CH2Cl2, -78 °C; aq. NH4Cl.
Figure 1. X-ray of Diels-Alder adduct 9.
unsaturated acyl oxazolidinone 7 was isolated in 81% yield
(E/Z selectivity >20:1). Azadiene 8 was synthesized by the
addition of 2.2 equiv of triethylsilyl triflate to an ethereal
suspension of glutarimide in the presence of Et3N (90% yield,
not shown).
With the appropriately functionalized bicycle in hand, our
investigations focused on the cleavage of the C1-N bond
to reveal the desired substituted cyclohexanone core. It was
found that treatment of 9 with n-Bu4NF preferentially induced
a retro-aldol scission of the C1-C2 bond.12 It was postulated
that removal of the oxazolidinone auxiliary might prevent
the undesired fragmentation (C1-C2). However, standard
methods to replace the auxiliary failed. Nucleophiles such
as LiSEt, LiOOH, and LiOMe preferentially added to the
urethane carbonyl of the acyl oxazolidinone, presumably as
a result of steric congestion around the imide carbonyl.
Fortunately, it was found that 9 could be converted to methyl
ester 10 using Sm(OTf)3 in refluxing MeOH. The success
of this reaction may be due to activation of the imide by
chelation of the Sm(III) cation with both carbonyl oxygens.13
To facilitate the desired C1-N bond scission, amide 10
was converted to the tert-butyl carbonate 11 using BOC2O,
DMAP conditions.14 The preference for O- over N-acylation
may be rationalized on the basis of steric effects. Subsequent
exposure of 11 to n-Bu4NF resulted in fragmentation to nitrile
The key hetero Diels-Alder reaction was performed by
combining oxazolidinone 7 and bistriethylsilyloxy azadiene
8 in the presence of 2.2 equiv of Me2AlCl at -78 °C. The
crystalline bicyclic adduct 9, as the desired exo diastereomer,
was isolated in 79% yield from a 20:1 diastereomeric
mixture.10 Scheme 2 depicts two possible transition states
for this reaction (TS1 and TS2) in which the oxazolidinone-
Lewis acid complex is highly organized as a result of
chelation of both carbonyl units of the acyl oxazolidinone
to the cationic aluminum. Presumably, this complexation
promotes ionization of the first equivalent of Me2AlCl with
concomitant generation of a second equivalent of anionic
Me2AlCl2.11 In this fixed conformation, the benzyl substituent
of the oxazolidinone effectively shields the bottom face of
(5) (a) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999, 121, 2617-2618.
(b) Ghosez, L.; Bayard, P.; Nshimyumukiza, P.; Gouverneur, V.; Sainte,
F.; Beaudegnies, R.; Rivera, M.; Frisque-Hesbain, A. M.; Wynants, C.
Tetrahedron 1995, 51, 11021-11042.
(6) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238-1256.
(7) 6-Chloropyridine-3-carboxyaldehdye (5) was prepared from from
6-chloronicotinc acid. See Supporting Information for details.
(8) Evans, D. A.; Johnson, J. S. J. Org. Chem. 1997, 62, 786-787.
Supporting Information.
(11) This chelation activation strategy using >2.0 equiv of Me2AlCl has
also been employed for additions to carbonyls; see: (a) Evans, D. A.;
Allison, B. A.; Yang, M. G. Tetrahedron Lett. 1999, 40, 4457-4460. (b)
Evans, D. A.; Halstead, D. P.; Allison, B. A. Tetrahedron Lett. 1999, 40,
4461-4462.
(12) Ghosez has observed a strong dependence of C-N vs C-C bond
scission on the electron withdrawing group at C2 in related 2-azabicyclo-
[2.2.2]octanones systems, see: Rivera, M.; Lamy-Schelkens, H.; Sainte,
F.; Mbiya, K.; Ghosez, L. Tetrahedron Lett. 1988, 29, 4573-4576.
(13) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.;
Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671-8726.
(14) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 38,
2424-2426.
(9) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
(10) Determined by 1H NMR analysis (500 MHz) of the unpurified
reaction mixture.
3010
Org. Lett., Vol. 3, No. 19, 2001

12, isolated exclusively as the enol tautomer, in 81% yield.15
Enol 12 was subjected to a Krapcho decarboxylation (DMSO,
H2O, 130 °C) to provide ketone 13 in 99% yield.16 A single-
crystal X-ray structure of 13 confirmed that the nitrile was
disposed in the axial position, cis to the chloropyridine ring.
Table 1. Diastereoselective Reductions of Ketone 15
entry
conditionsa
solvent
T, °C
16:17c
Scheme 3. Bicycle Fragmentationa
1
2
3
4
L-Selectrideb
i-Bu2AlH
LiBH4
Et2O
CH2Cl2
THF
-78
-78
-78
-40
75:25
65:35
86:14
92:8d
NaBH4
MeOH
a All reactions were 0.1 M in substrate and proceeded to g95%
conversion. b L-Selectride ) lithium tri-sec-butylborohydride. c Product
ratios were determined by 1H NMR (500 MHz, 60 °C). d Isolated yield of
16/17 ) 89%
molecular SN2 displacement by nitrogen would follow.
Although the reduction proceeded without affecting the
chloropyridine ring,21 a 75:25 mixture of inseparable alcohols
was obtained. The structural assignment of the major
diastereomer was complicated as a result of slowly inter-
1
converting conformations as observed by H NMR spec-
troscopy, even at elevated temperatures. Ultimately, the major
isomer was determined to be equatorial alcohol 16 by the
straightforward conversion of minor isomer 17 to epibatadine
(1) by a three-step sequence.22 Although hindered hydride
reagents did not produce the desired axial alcohol, relatively
smaller reducing agents afforded the equatorial alcohol with
good selectivity (Table 1). Whereas lithium borohydride was
modestly selective for alcohol 16 (86:14; entry 3), the
treatment of ketone 15 with NaBH4 in MeOH at -40 °C
(entry 4) afforded an 89% yield of alcohols 16/17 as a 92:8
mixture favoring 16. These experiments seem to indicate that
conformational effects play an important role in the stereo-
chemical outcome of this reduction.
a Reaction conditions: (a) Sm(OTf)3, MeOH, reflux. (b) BOC2O,
DMAP, Et3N, CH2Cl2. (c) n-Bu4NF, THF/H2O. (d) DMSO, H2O,
130 °C. (e) Me3SiOK, toluene, 70 °C; aq. NH4Cl; (f) Pb(OAc)4,
tert-butyl alcohol, 50 °C.
The completion of the synthesis required inverting the
equatorial alcohol 16 in order to facilitate subsequent closure
to the 7-azabicylco[2.2.1]heptane system. Accordingly, al-
cohols 16/17 were converted into the corresponding mesy-
lates (MsCl, Et3N) from which 18 was isolated in high yield
(92%). Subsequent SN2 displacement (LiBr, THF, 50 °C)
furnished bromide 19 in 84% yield (Scheme 4). Treatment
of bromide 19 with trifluoroacetic acid provided the primary
amine 20 in 91% yield. Finally, penultimate amine 20 was
heated at reflux in CHCl3 for 3 days to afford (-)-epibatidine
The synthesis now required the transposition of nitrogen
from the nitrile to a protected amine, as well as a stereo-
selective ketone reduction. The conversion of nitrile 13 to
the derived primary amide 14 was accomplished in 72% yield
with potassium trimethylsilanolate in toluene at 70 °C.17
Amide 14 was then subjected to lead(IV) acetate in tert-
butyl alcohol, which induced a Hofmann rearrangement to
afford the BOC-protected amine 15 in 70% yield.18
Initial attempts to reduce ketone 15 utilized sterically
demanding hydride reagents such as L-Selectride19 (Table
1).20 The anticipated axial alcohol (trans with respect to the
protected nitrogen) could then be activated, and an intra-
(1, [R]25 -6.7° (c 0.21, CH2Cl2))23 in 95% yield. The
D
structure of synthetic 1 was confirmed by comparison to
reported literature data (1H, 13C NMR, IR).24
(15) (a) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967,
6, 1-106. (b) Weyerstahl, P.; Marschall, H. Fragmentation Reactions. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 6, pp 1041-1070.
(20) For a review on the origin of stereoselectivity of metal hydride
additions to cyclohexanones, see: Gung, B. W. Tetrahedron 1996, 52,
5263-5301.
(21) Undesired reduction of the chloropyridine ring has complicated
previous syntheses; see: (a) Sirisoma, N. S.; Johnson, C. R. Tetrahedron
Lett. 1998, 39, 2059-2062. (b) Palmgren, A.; Larsson, A. L. E.; Ba¨ckvall,
J.-E.; Helquist, P. J. Org. Chem. 1999, 64, 836-842.
(22) The mixture of alcohols 16 and 17 were converted to the mesylates
(MsCl, Et3N, 92%), the BOC protecting groups were removed with 10%
trifluoroacetic acid in CH2Cl2 (95%), and the amines were heated in
refluxing chloroform to afford a separable 3:1 mixture of mesylate and (-)-
epibatidine.
(16) Krapcho, A. P. Synthesis 1982, 805-822.
(17) (a) Merchant, K. J. Tetrahedron Lett. 2000, 41, 3747-3749. (b)
Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831-5834.
(18) (a) Baumgarten, H. E.; Staklis, A. J. Am. Chem. Soc. 1965, 87,
1141-1142. (b) Wallis, E. S.; Lane, J. F. The Hofmann Reaction; John
Wiley: New York, 1946; Vol. 3, pp 267-306.
(19) Brown, H. C.; Krishnamurthy, S. J. Am. Chem. Soc. 1972, 94, 7159-
7161.
Org. Lett., Vol. 3, No. 19, 2001
3011

tation. The route described here demonstrates the powerful
utility of Me2AlCl-promoted Diels-Alder reactions of 2-aza-
dienes and R,â-unsaturated imides for the synthesis of
alkaloids.
Scheme 4. Completion of the Synthesisa
Acknowledgment. Support for this research has been
provided by the NSF and National Institutes of Health (GM
33328-18). The NIH is acknowledged for a postdoctoral
fellowship support (K.A.S.). We wish to thank Dr. Mick Dart
of Abbott Laboratories for providing a sample of racemic
epibatidine. The NIH Shared Instrumentation Grant Program
(1-S10-RR04870) and the NSF (CHE 88-14019) are ac-
knowledged for providing NMR facilities.
a Reaction conditions: (a) MsCl, Et3N, CH2Cl2; (b) LiBr, THF,
50 °C; (c) CF3COOH, CH2Cl2; (d) CHCl3, reflux.
Supporting Information Available: Experimental pro-
cedures for all new compounds and X-ray crystallographic
data for 9 and 13. This material is available free of charge
via the Internet at http://pubs.acs.org.
In summary, a highly selective asymmetric synthesis of
(-)-epibatidine has been achieved in 13 steps and 13%
overall yield from 6-chloropyridine-3-carboxyaldehdye. The
key steps include a Lewis acid mediated exo-selective hetero
Diels-Alder reaction and an unusual ring-opening fragmen-
OL016420Q
(24) (a) Aoyagi, S.; Tanaka, R.; Naruse, M.; Kibayashi, C. J. Org. Chem.
1998, 63, 8397-8406. (b) Zhang, C.; Trudell, M. L. J. Org. Chem. 1996,
61, 7189-7191. (c) Pandey, G.; Bagul, T. D.; Sahoo, A. K. J. Org. Chem.
1998, 63, 760-768.
(23) Reported literature optical rotation value for (-)-epibatidine: [R]25
D
-6.2° (c 0.42, CH2Cl2). Trost, B. M.; Cook, G. R. Tetrahedron Lett. 1996,
37, 7485-7488.
3012
Org. Lett., Vol. 3, No. 19, 2001